Activin-A overexpression in the murine lung causes pathology that simulates acute respiratory distress syndrome.

RATIONALE: Activin-A is up-regulated in various respiratory disorders. However, its precise role in pulmonary pathophysiology has not been adequately substantiated in vivo. OBJECTIVES: To investigate in vivo the consequences of dysregulated Activin-A expression in the lung and identify key Activin-A-induced processes that contribute to respiratory pathology. METHODS: Activin-A was ectopically expressed in murine lung, and functional, structural, and molecular alterations were extensively analyzed. The validity of Activin-A as a therapeutic target was demonstrated in animals overexpressing Activin-A or treated with intratracheal instillation of LPS. Relevancy to human pathology was substantiated by demonstrating high Activin-A levels in bronchoalveolar lavage (BAL) samples from patients with acute respiratory distress syndrome (ARDS). MEASUREMENTS AND MAIN RESULTS: Overexpression of Activin-A in mouse airways caused pulmonary pathology reminiscent of acute lung injury (ALI)/ARDS. Activin-A triggered a lasting inflammatory response characterized by acute alveolar cell death and hyaline membrane formation, sustained up-regulation of high-mobility group box 1, development of systemic hypercoagulant state, reduction of surfactant proteins SpC, SpB, and SpA, decline of lung compliance, transient fibrosis, and eventually emphysema. Therapeutic neutralization of Activin-A attenuated the ALI/ARDS-like pathology induced either by ectopic expression of Activin-A or by intratracheal instillation of LPS. In line with the similarity of the Activin-A-induced phenotype to human ARDS, selective up-regulation of Activin-A was found in BAL of patients with ARDS. CONCLUSIONS: Our studies demonstrate for the first time in vivo the pathogenic consequences of deregulated Activin-A expression in the lung, document novel aspects of Activin-A biology that provide mechanistic explanation for the observed phenotype, link Activin-A to ALI/ARDS pathophysiology, and provide the rationale for therapeutic targeting of Activin-A in these disorders.

Toll-like receptor 7-triggered immune response in the lung mediates acute and long-lasting suppression of experimental asthma.

RATIONALE: Toll-like receptor (TLR) 7/8 ligands are promising candidate drugs for the treatment of allergic asthma and rhinitis. Although their clinical application depends on the development of strategies for topical administration to the lung, this has not been explored in preclinical disease models. OBJECTIVES: To examine the therapeutic effectiveness, persistence of effect, and mode of action of intranasal TLR7 ligand administration in allergic airway disease. METHODS: Wild-type, IFN-alpha receptor (IFN-alphaR)(-/-), IFN-gamma(-/-), CD8(-/-), TLR7(-/-), and radiation-induced chimeric mice deficient in hematopoietic TLR7 expression were subjected to an established model of allergic airway disease. R-848, a specific TLR7 agonist in mice, was administered prophylactically or therapeutically and effects of treatment on helper T-cell type 2 (Th2) responses, eosinophilia, goblet cell metaplasia, and airway hyperresponsiveness were assessed. MEASUREMENTS AND MAIN RESULTS: Intranasal R-848 administration induced a transient immune response characterized by type I interferon production and infiltration of innate immune cells into the lung. This conferred long-term suppression of allergic airway disease via two complementary molecular processes, one mediated by type I interferons and providing acute protection by directly inhibiting effector Th2 responses, and one mediated by immunoregulatory CD8(+) T cells and inducing long-lasting protection by suppressing Th2 responses in an IFN-gamma-dependent manner. CONCLUSIONS: Intranasal R-848 administration is an effective treatment for allergic airway disease. It hijacks an otherwise proinflammatory immune process triggered by TLR7 to mediate long-lasting disease suppression. This provides important insight into the efficacy and mode of action of TLR7 ligands in murine models of allergic airway disease and paves the way for their clinical application in humans.

Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration.

Dickkopf-1 is an inhibitor of Wnt signaling, which is crucial for osteoblast differentiation. We evaluated serum levels of Dickkopf-1 in 66 patients with thalassemia-induced osteoporosis who received therapy with zoledronic acid in a placebo-controlled, randomized trial. At baseline, thalassemia patients had increased serum levels of Dickkopf-1 that correlated with reduced bone mineral density of the lumbar spine and the distal radius. High Dickkopf-1 also correlated with increased bone resorption and reduced bone formation markers. Zoledronic acid produced a reduction in serum Dickkopf-1, which was associated with bone mineral density increase after 12 months of therapy. On the contrary, placebo group showed a borderline increase of Dickkopf-1, which was higher in patients who showed deterioration in pain scores. These results suggest that Dickkopf-1 is implicated in the pathogenesis of osteoporosis in thalassemia and reveal Dickkopf-1 as a possible target for the development of novel agents for the management of thalassemia-induced osteoporosis.